tbuckley/cabot-search huggingface dataset:
The evidence base for US joint commission hospital accreditation standards: cross sectional study
Authors: Sarah A Ibrahim, Kelly A Reynolds, Emily Poon, Murad Alam
Journal: BMJ (2022)

To evaluate the evidence upon which standards for hospital accreditation by The Joint Commission on Accreditation of Healthcare Organizations (the Joint Commission) are based.Cross sectional study.United States.Four Joint Commission R3 (requirement, rationale, and reference) reports released by July 2018 and intended to become effective between 1 July 2018 and 1 July 2019.From each R3 report the associated standard and its specific elements of performance (or actionable standards) were extracted. If an actionable standard enumerated multiple requirements, these were separated into distinct components. Two investigators reviewed full text references, and each actionable standard was classified as either completely supported, partly supported, or not supported; Oxford evidence quality ratings were assigned; and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to assess the strength of recommendations.Strengths of recommendation for actionable standards.20 actionable standards with 76 distinct components were accompanied by 48 references. Of the 20 actionable standards, six (30%) were completely supported by cited references, six were partly supported (30%), and eight (40%) were not supported. Of the six directly supported actionable standards, one (17%) cited at least one reference of level 1 or 2 evidence, none cited at least one reference of level 3 evidence, and five (83%) cited references of level 4 or 5 evidence. Of the completely supported actionable standards, strength of recommendation in five was deemed GRADE D and in one was GRADE B.In general, recent actionable standards issued by The Joint Commission are seldom supported by high quality data referenced within the issuing documents. The Joint Commission might consider being more transparent about the quality of evidence and underlying rationale supporting each of its recommendations, including clarifying when and why in certain instances it determines that lower level evidence is sufficient.
Safety and Immunogenicity of mRNA Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Lung Cancer Receiving Immune Checkpoint Inhibitors: A Multicenter Observational Study in Japan
Authors: Makoto Hibino, Kiyoaki Uryu, Takayuki Takeda, Yusuke Kunimatsu, Shinsuke Shiotsu, Junji Uchino, Soichi Hirai, Tadaaki Yamada, Asuka Okada, Yoshikazu Hasegawa, Osamu Hiranuma, Yusuke Chihara, Riko Kamada, Shunichi Tobe, Kazunari Maeda, Shigeto Horiuchi, Tetsuri Kondo, Koichi Takayama
Journal: Journal of Thoracic Oncology (2022)

Patients with cancer have been prioritized for vaccination against severe acute respiratory syndrome coronavirus 2. Nevertheless, there are limited data regarding the safety, efficacy, and risk of developing immune-related adverse events (irAEs) associated with mRNA vaccines in patients with lung cancer, especially those being actively treated with immune checkpoint inhibitors. This multicenter observational study was conducted at nine hospitals in Japan. Patients with lung cancer (≥20 y) actively treated with immune checkpoint inhibitors between 4 weeks prefirst vaccination and 4 weeks postsecond vaccination were enrolled. The primary end point was the incidence of irAEs of any grade on the basis of an assumed incidence without vaccination rate of 35%. Immunogenicity was assessed by measuring anti-spike (S)-IgG antibody levels against severe acute respiratory syndrome coronavirus 2. A total of 126 patients with lung cancer (median age, 71 y; interquartile range, 65-74) were enrolled from May to November 2021 and followed up until December 2021. There were 26 patients (20.6%, 95% confidence interval: 13.9%-28.8%) and seven patients (5.6%, 95% confidence interval: 2.3%-11.1%) who developed irAEs of any grade pre- and postvaccination, respectively, which was lower than the predicted incidence without vaccination. None of the patients experienced exacerbation of preexisting irAE postvaccination. S-IgG antibodies were seroconverted in 96.7% and 100% of the patients with lung cancer and controls, respectively, but antibody levels were significantly lower in patients with lung cancer (p < 0.001). Patients with lung cancer who were actively treated with ICIs were safely vaccinated without an increased incidence of irAEs; however, their vaccine immunogenicity was lower. This requires further evaluation.
Associations of Pre- and Postnatal Air Pollution Exposures with Child Behavioral Problems and Cognitive Performance: A U.S. Multi-Cohort Study
Authors: Yu Ni, Christine T. Loftus, Adam A. Szpiro, Michael T. Young, Marnie F. Hazlehurst, Laura E. Murphy, Frances A. Tylavsky, W. Alex Mason, Kaja Z. LeWinn, Sheela Sathyanarayana, Emily S. Barrett, Nicole R. Bush, Catherine J. Karr
Journal: Environmental Health Perspectives (2022)

Population studies support the adverse associations of air pollution exposures with child behavioral functioning and cognitive performance, but few studies have used spatiotemporally resolved pollutant assessments.We investigated these associations using more refined exposure assessments in 1,967 mother-child dyads from three U.S. pregnancy cohorts in six cities in the ECHO-PATHWAYS Consortium.Pre- and postnatal nitrogen dioxide (NO2) and particulate matter (PM) ≤2.5μm in aerodynamic diameter (PM2.5) exposures were derived from an advanced spatiotemporal model. Child behavior was reported as Total Problems raw score using the Child Behavior Checklist at age 4-6 y. Child cognition was assessed using cohort-specific cognitive performance scales and quantified as the Full-Scale Intelligence Quotient (IQ). We fitted multivariate linear regression models that were adjusted for sociodemographic, behavioral, and psychological factors to estimate associations per 2-unit increase in pollutant in each exposure window and examined modification by child sex. Identified critical windows were further verified by distributed lag models (DLMs).Mean NO2 and PM2.5 ranged from 8.4 to 9.0 ppb and 8.4 to 9.1 μg/m3, respectively, across pre- and postnatal windows. Average child Total Problems score and IQ were 22.7 [standard deviation (SD): 18.5] and 102.6 (SD: 15.3), respectively. Children with higher prenatal NO2 exposures were likely to have more behavioral problems [β: 1.24; 95% confidence interval (CI): 0.39, 2.08; per 2 ppbNO2], particularly NO2 in the first and second trimester. Each 2-μg/m3 increase in PM2.5 at age 2-4 y was associated with a 3.59 unit (95% CI: 0.35, 6.84) higher Total Problems score and a 2.63 point (95% CI: -5.08, -0.17) lower IQ. The associations between PM2.5 and Total Problems score were generally stronger in girls. Most predefined windows identified were not confirmed by DLMs.Our study extends earlier findings that have raised concerns about impaired behavioral functioning and cognitive performance in children exposed to NO2 and PM2.5in utero and in early life. https://doi.org/10.1289/EHP10248.
Error in Figures 1 and 2
Journal: JAMA Network Open (2022)

Arvid Edén, MD, PhD; Anna Grahn, MD, PhD; Daniel Bremell, MD, PhD; Anahit Aghvanyan, MD; Pradeepthi Bathala, MS; Dietmar Fuchs, PhD; Johanna Gostner, PhD; Lars Hagberg, MD, PhD; Nelly Kanberg, MD; Sunsanee Kanjananimmanont, MS; Magnus Lindh, MD, PhD; Salvia Misaghian, MS; Staffan Nilsson, PhD; Michael Schöll, PhD; George Sigal, PhD; Erika Stentoft, MD; Marie Studahl, MD, PhD; Aylin Yilmaz, MD, PhD; Mingyue Wang, MD; Martin Stengelin, PhD; Henrik Zetterberg, MD, PhD; Magnus Gisslén, MD, PhD
P761: MONOCYTOSIS IN PRIMARY CARE AND HEMATOLOGICAL MALIGNANCIES
Authors: M. Christensen, V. Siersma, M. Kriegbaum, B. Lind, J. Samuelsson, K. Grønbæk, L. Granfeldt, C. L. Andersen
Journal: HemaSphere (2022)

Background: Monocytosis (blood monocyte count > 0.8 x109/L) is relatively often observed in routine blood work from primary care, however, the significance is not always apparent as monocytosis may be present in a spectrum of diseases spanning from mild infections to chronic myelomonocytic leukemia. Aims: We aimed to examine the predictive value of monocytosis in primary care by relating monocyte count to subsequent 3-year incidence of hematological malignancy. Methods: We included 663.184 adult patients from primary care in the greater Copenhagen Area who had a complete blood cell count (CBC) performed at any time between 2000-2016. For patients with multiple samples registered, a random sample was selected and samples predating the index CBC by 3 months were assessed to account for sustained monocytosis. Using the extensive Danish health data registers, we collected data on incident hematological malignancy for 3 years following the CBC. We modelled the association between monocyte count and hematological malignancies as well as all-cause mortality using multiple logistic regression analysis. Results: Monocytosis was observed in 4,6 % of CBCs. We saw an increased risk of myeloid malignancies with the most noticeable being an odds ratio (OR) for CMML > 100 with monocytosis > 1.0 x 109/L. Sustained monocytosis increased this risk to OR >140. The incidence was, however, still low with only 0.1% of patients with monocytosis developing CMML within 3 years. Risk of lymphoproliferative and M-component related diseases were also increased, however, other relevant cell line were affected as well in these cases. Summary/Conclusion: Monocytosis is a common finding in primary care, but even with monocytosis > 1 x 109/L hematological malignancies are rare. Optimized referral to secondary care remains a challenge and if the clinical presentation leaves doubt of the diagnosis, repeated measurements help demask if malignancy is the cause of the monocytosis.
Gene amplification‐driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A‐YTHDF2‐dependent in lung adenocarcinoma
Authors: Chang Zhang, Qi Sun, Xu Zhang, Na Qin, Zhening Pu, Yayun Gu, Caiwang Yan, Meng Zhu, Juncheng Dai, Cheng Wang, Ni Li, Guangfu Jin, Hongxia Ma, Zhibin Hu, Erbao Zhang, Fengwei Tan, Hongbing Shen
Journal: Cancer Communications (2022)

Abstract Background Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6‐methyladenosine (m6A) RNA modification regulates gene expression and cell fate. However, the reasons for activation of KIAA1429 (also known as VIRMA, an RNA methyltransferase) and its underlying mechanism in lung adenocarcinoma (LUAD) remain largely unexplored. In this study, we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD. Methods Whole‐genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase. The in vitro and in vivo functions of KIAA1429 were investigated. Transcriptome sequencing, methylated RNA immunoprecipitation sequencing (MeRIP‐seq), m6A dot blot assays and RNA immunoprecipitation (RIP) were performed to confirm the modified gene mediated by KIAA1429. RNA stability assays were used to detect the half‐life of the target gene. Results Copy number amplification drove higher expression of KIAA1429 in LUAD, which was correlated with poor overall survival. Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD. Mechanistically, the target genes of KIAA1429‐mediated m6A modification were confirmed by transcriptome sequencing and MeRIP‐seq assays. We also revealed that KIAA1429 could regulate BTG2 expression in an m6A‐dependent manner. Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2, the m6A “reader”)‐dependent BTG2 mRNA stability and promoted the expression of BTG2; thus, participating in the tumorigenesis of LUAD. Conclusions Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis, which may provide a novel view on the targeted molecular therapy of LUAD.
P477: PHENOTYPICALLY-DEFINED STAGES OF LEUKEMIA ARREST PREDICT MAIN DRIVER MUTATIONS SUBGROUPS, AND OUTCOME IN ACUTE MYELOID LEUKEMIA
Authors: F. Vergez, L. Largeaud, S. Bertoli, M.-L. Nicolau-Travers, J.-B. Rieu, I. Vergnolle, E. Saland, A. Sarry, S. Tavitian, F. Huguet, M. Picard, J.-P. Vial, N. Lechevalier, A. Bidet, P.-Y. Dumas, A. Pigneux, I. Luquet, V. Mansat-De Mas, E. Delabesse, M. Carroll, G. Danet-Desnoyers, J.-E. Sarry, C. Recher
Journal: HemaSphere (2022)

Background: Normal blood cell maturation is organized according to a functional hierarchy at the top of which are multipotent hematopoietic stem cells (HSC). Immunophenotypically, human HSC are enriched in a population of Lin-, CD34+, CD38-, CD90+, CD45RA- cells. Upon differentiation, HSC give rise to multipotent progenitors (MPP), which retain the ability to produce all blood lineages but have lost their self-renewal capacity. The classical model of hematopoiesis postulates that MPP are then orientated toward either the lymphoid or myeloid lineage, developing into common myeloid progenitors (CMP) or lymphoid-primed multipotent progenitors (LMPP) which can still produce defined myeloid cell types. Along the myeloid pathway, CMP can differentiate into either granulocyte-monocyte progenitors (GMP) or megakaryocyte-erythroid progenitors (MEP). GMPs finally differentiate into granulocyte progenitors (GP) or monocyte progenitors (MP). Aims: In this study, we hypothesized that the stages of leukemic arrest (SLA) in myeloid maturation can be defined by flow cytometry by analogy with the stages of hematopoiesis and they correlate with the oncogenic events implicated in the mechanism of differentiation block. Methods: Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO and HLA-DR expression by flow cytometry were identified in 2 independent fully annoted cohorts of 2087 and 1209 AML patients. Next-generation sequencing was performed in 409 AML patients. Results: HSC/MPP-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas GMP-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in GP-like AML or with DNMT3A mutations in MP-like AML. Image:Summary/Conclusion: AML immunophenotyping can establish a new SLA classification that strongly correlates with cellular behaviour of the leukemic bulk, predicts main genetic subgroups early at diagnosis and outcome after intensive chemotherapy. Each SLA is defined by specific oncogenic events whose penetrance may be dependent on the differentiation stages of hematopoiesis and their gene expression. Identifying disrupted gene pathways specific for each SLA should therefore form the basis for targeted therapies aimed at inducing AML differentiation.
P994: HEDGEHOG PATHWAY INVOLVEMENT IN MASTOCYTOSIS DEVELOPMENT
Authors: L. Polivka, V. Parietti, J. Bruneau, E. Soucie, P. Dubreuil, C. Bodemer, O. Hermine, L. Maouche Chretien
Journal: HemaSphere (2022)

Background: Mastocytosis is a rare and heterogenous disease characterized by abnormal accumulation and activation of mast cells in one or several organs. The clinical spectrum of the pathology varies from relatively mild forms with isolated skin lesions to very aggressive forms with wide systemic involvement, often fatal. The disease can affect both children and adults. While most pediatric forms resolve during or in late puberty, adult cases are persistent and may evolve into aggressive forms. A somatic KIT D816V mutation is detected in 85% of patients but all attempts to demonstrate its oncogenic effect have failed. There is strong evidence that the KIT D816V mutation alone cannot trigger the disease and that other genes may be involved. Aims: The French national reference center of mastocytosis (CEREMAST) has recorded more than 2000 patients with sporadic mastocytosis and 60 familial cases. Since KIT mutations do not fully explain the pathophysiology of the disease, we sought to identify other mutations that could act synergistically with KIT D816V to induce the disease. Methods: We focused on patients presenting with mastocytosis in particular syndromic contexts within the pediatric cohort followed at Necker hospital; we first investigated the molecular mechanisms underlying mastocytosis onset in patients with both congenital mastocytosis and an extremely rare polymalformative syndrome. Results: From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS) and congenital mastocytosis, we could demonstrate the implication of the hedgehog (Hh) pathway in mastocytosis. GCPS is a very rare syndrome resulting from haploinsufficiency of GLI3, the major repressor gene of the hedgehog (Hh) family. We showed that the Hh pathway is barely active in normal primary mast cells (MCs) and overactive in neoplastic MCs. Using a GCPS mouse model, we demonstrated that mutations in GLI3 and KIT have a synergistic, tumorigenic effect leading to mastocytosis onset. We also showed that Hh inhibitors suppress abnormal mast cell proliferation, in vitro, and extend the survival of mice with aggressive systemic mastocytosis (ASM). Summary/Conclusion: Thus, for the first time, we revealed the involvement of Hh signaling pathway in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM. Finally, we provided the first evidence that Hh inhibitors represent a promising new therapeutic target.
P823: THE INCIDENCE, OUTCOMES, AND RISK FACTORS OF SECONDARY POOR GRAFT FUNCTION IN HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA
Authors: F. lin, T. han, Y. zhang, Y. cheng, Z. xu, X. mo, F. wang, C. yan, Y. sun, J. wang, F. tang, W. han, Y. chen, Y. wang, X. zhang, K. liu, X. huang, L. xu
Journal: HemaSphere (2022)

Background: Secondary poor graft function (sPGF) increases the risk of life-threatening complications after transplantation and is an obstacle to achieving better outcomes after hematopoietic stem cell transplantation (HSCT). Aims: We aimed to determine the incidence, clinical outcomes, and risk factors of sPGF in haploidentical HSCT (haplo-HSCT) for acquired aplastic anemia (AA) patients. Methods: We retrospectively reviewed 430 consecutive AA patients receiving haplo-HSCT in Peking University People’s Hospital between January 2006 and December 2020. Results: We reported the estimated 3-year cumulative incidence of sPGF was 4.64%, while no primary PGF occurred. The median time to sPGF was 121 days (range 30-626 days) after transplantation. To clarify the risk factors for sPGF, 17 sPGF cases and 382 without PGF were further analyzed. Compared to patients without PGF, the 2-year overall survival was significantly poorer for sPGF patients (67.7% vs 90.8%, p =.002). Twelve sPGF patients were alive until the last follow-up, and 7 achieved transfusion independency. The multivariable analyses revealed that a history of refractory cytomegalovirus viremia (CMViremia) (OR=7.038, p=.002) post-transplantation independently increased the risk of sPGF. There was weak evidence that a history of grade 3-4 acute graft-versus-host disease (aGvHD) increased the risk of sPGF (p=.092). Summary/Conclusion: In conclusion, sPGF can develop in 4.64% of AA patients after haplo-HSCT and significantly decreases survival. The independent hazard elements for sPGF were a history of refractory CMViremia and grade 3-4 aGvHD. We advocated better post-transplantation strategies to balance the risk of immunosuppression and viral reactivation for haplo-HSCT in AA patients.
Multicentre Selective Lymphadenectomy Trial 1: key primary data remain unavailable
Authors: Anthony Dixon, Athanassios Kyrgidis, Christopher Zachary, John Dixon, Catalin Popescu, Michael Sladden, Zoe Apalla, Stuart Anderson, Giuseppe Argenziano, Demitrios Ioannides, Alexander Nirenberg, Aimillios Lallas, Samuel Zagarella, Caterina Longo, Harvey Smith, Howard Steinman, Thrasivoulos Tzellos, Lloyd Cleaver, Ken Leahey, Christos C. Zouboulis, J. Meirion Thomas
Journal: British Journal of Dermatology (2022)
P523: MIDOSTAURIN PLUS INTENSIVE CHEMOTHERAPY IN FLT3 MUTATED AML. “REAL LIFE” DATA VERSUS THE RATIFY STUDY
Authors: A. De La Fuente, M. Diaz Beya, P. Beneit, C. Botella, A. Fernandez Moreno, A. Sampol, M. Arnan Sangerman, A. Yeguas Bermejo, M. D. L. L. Amigo, J. Labrador, A. Garcia Guinon, A. Garrido, J. Serrano, S. Vives Polo, M. Garcia Fortes, M. J. Sayas, J. M. Bergua, M. T. Olave, F. Vall LLovera, J. Bargay, M. Pereiro Sanchez, R. Garcia Boyero, A. Diaz Lopez, M. Tormo
Journal: HemaSphere (2022)

Background: FLT3 mutation is associated with adverse prognosis in AML (ELN2017, Dohner et al, Blood 2017) and Intensive chemotherapy (IC) has been the standard of treatment for FLT3 mutated AML for decades. Midostaurin (Midos) has been approved in combination with IC for FLT3-mutated AML based on an improvement in overall survival noted in the RATIFY phase 3 trial (Stone et al, N Engl J Med 2017) Aims: The aims of this study are to analyze safety and effectiveness of Midos plus IC in FLT3 AML, to validate RATIFY results in a “real-world” setting and to identify risk factors. Methods: We carried out a retrospective multicenter study (MDA-AML-2018-06) in 27 Spanish centers. Inclusion criteria: age >18 years, FLT3-mutated AML diagnosis according to WHO criteria and start of treatment with midostaurin in combination with IC between June 2016 and June 2021. We evaluated the response according to 2017 ELN criteria, toxicity according to CTCAE v4.0 and overall survival (OS) by Kaplan-Meier. Statistical analysis was performed using SPSS program version 20.0. Results: A total of 175patients (pt) were included (93 female), median age 53 (18-76), of them 111were younger than 60yrs and 110pts had ECOG<2. ELN2017 stratification was favorable in 53pt; Intermediate: 72pt; adverse in 26pt. Median WBC count 44.500/µL (0.4-395.000). A total of 133pts had FLF3-ITD mutation and of them 74pt with ratio ≥0.5. Safety: Total Midos cycles 548 (median 2), 20 pt (11.5%) suffered QT prolongation, 26pt (14,8%) Midos interruption and 10pt (5.7%) Midos reduction. There were no deaths related to Midos. Effectiveness: 144 (81.4%) pt achieved CR after Induction1or2, of them 76pt were consolidated with alloSCT, 24pt received maintenance and 41pt proceed to W&W. Median OS for the whole population was not reached and the 24months OS was 68%. In our experience ELN2917 classification and ECOG<2 identify groups with differences in OS (p0.019 and p0.04 respectively). Age <60vs≥60 resulted in no differences for OS. We observed significant differences for maintenance versus W&W (p=0.001) in favorable and intermediate risk patients. Comparing maintenance vs alloSCT we observe no differences in the Intermediate ELN2017 group. Image:Summary/Conclusion: Our experience confirms safety and effectiveness of Midos plus IC as first line in FLT3 AML patients with similar 2yOS as the previous reported in the RATIFY trial. Interesting that in our experience age 60 and above resulted in no differences for OS.